SMALLPOX

1. SMALLPOX Terrorism, Science, Values, Choice, Public Health and Public Policy Health Systems Face UNCERTAINTY William J. Bicknell, MD, MPH School of Public Health Boston University

2. The US Issues • The Risk of Attack? • If an attack, the magnitude? • If an attack, can ring containment & quarantine work? • Vaccine risks? • Liability issues? • Are there responsible alternative options? • Who should decide what?

3. Issues in Other Countries • Risk of Attack • Risk of Secondary Spread • Risks & Benefits of Vaccination • Vaccine Effectiveness Pre & Post Exposure • Prevalence of Immunocompromised persons • Medical Care Delivery System Capacity • National Wealth • Opportunity Costs & Competing Priorities • Other?

4. Today • Facts • Myths and controversies • What the US is doing • Where it was just after 911 • Where it is today • A Decision Analysis & Policy Framework for other countries

5. Challenges • Very limited current knowledge & experience about smallpox • No one has epidemic control in a non-immune population experience • Relevance of lessons from eradication experience (characterized by very different circumstances) is likely to be more limited than realized

6. The Risk of Attack • What was our estimate of 9/11 on 9/10? • I have never heard any informed person state with confidence that smallpox has not been disseminated outside the two repositories • There are reports of vaccination of N.Korean and Iraqi troops • US, UK, Israel, Germany & Australia and perhaps others are acquiring vaccine. • Israelis vaccinating first responders • The US has enough for vaccine for all residents • US is vaccinating first responders (more later) • Bottom line - Unknown but non-trivial risk of terrorist attack • Therefore, we need to know something about smallpox, let’s get some basics

7. Off the Wall? • Dr. Fenner: No errors and “A good case, reasonable for America” and last Friday he said he thought the framework for other countries made sense. • Dr. Fauci: With regard to the US “….excellent and hopefully will generate some frank and needed discussion. The stepwise approach that you recommend makes sense and is quite reasonable….”

8. Smallpox Disease • Highly Infectious • It is dangerous and in error to say or believe otherwise • Mortality5% to > 50% - usually ~25% • 60% - 80% of survivors disfigured • Highest in young children • No specific treatment • ~ 50% of US and most populations not immune • ~ 50% may have some residual immunity • How much immunity ? No one really knows • An historical note: The Aztecs & Incas, immunologically & genetically naïve, lost to smallpox not the Spanish & Portuguese* *F. Fenner 10/11/02

9. Smallpox Transmission 1 • Incubation - not infectious 10 -12 days • Last days of incubation you feel lousy with Fever • Then fever drops and you feel better but not well and are infectious • Usually no visible rash yet - just inside mouth and throat • Classic rash still 2 to 4 days away • Message - Highly infectious, not very visible or obvious and not necessarily very sick • Remember terrorists are motivated folks and can be expected to walk and disseminate even though feeling ill

10. Smallpox transmission 2 • Close contacts are “best” - within 6 feet • Think of the morning metro or many other places • How easy is it to transmit? • Let’s consider some historical examples

11. A Chilling Scenario • “One person with smallpox arriving in the country traveled by train….he was apparently in the initial phase of the disease, as nobody noticed a rash on his face…Almost everyone who traveled with him in the compartment from Queensborough to Manchester contracted smallpox, the ticket collector...and those who traveled with him to Stalybridge in another train, something like a hundred people being infected from one single case.” • Not so different from flying in from Europe, traveling downtown by public transport and taking a train to the next city • And terrorists are very motivated, so expect them to travel even if feeling quite ill Wanklyn (1913) cited in Dixon p311

12. More Examples • Other documented examples • Yugoslavia 1972 “..denied (having a) rash..no evidence of skin lesions” 11 secondary cases • Tripoli 1946 “…a highly modified attack..unrecognized… gives rise to… fatal attacks ” A smuggler infects wife and child • Walking by a window and similar examples are found in the literature • Also true this is not always the case - but should we count on good luck? • Worse yet, aerosol by immune disseminators. • Experts I have spoken with feel, technically, this is feasible to expect in a terrorist attack.

13. Possible Attack Rates in Terrorist Contacts Something between 10% & 50% may be a reasonable assumption Dixon, p310

14. The four day window • Evidence fromTripoli in 1946 (Dixon 12/48, 369-370) 21 non-immunes vaccinated within 5 days, all acquired smallpox, most mild, none died • Anecdotal evidence from the eradication years that the disease is less severe if vaccination within 4 days of contact • Vaccination within the window may prevent death and may prevent some disease • But the vaccinator has to find and vaccinate the infected persons • Contact tracing not likely to begin until 14 to 17 days after first exposure. In most situations, finding initial contacts within 4 days is impossible

15. “The Race to Trace”* • “Contact identification is the most urgent task when investigating smallpox cases since vaccination of close contacts as soon as possible following exposure but preferably within 3-4 days may prevent or modify disease. This was the successful strategy used for the global eradication of smallpox.” CDC Interim Plan, Guide A, p. A-10 • A race that cannot be won in a terrorist scenario • An excellent example of DO NOT ALWAYS BELIEVE THE EXPERTS *Kaplan, Craft & Wein

16. A Recent Mathematical Model(Kaplan -Yale, Craft - MIT, Wein - Stanford) • Clearly demonstrates the limits and inadequacies of the CDC recommendation for ring containment. • CDC has not yet adequately acknowledged and needs to update and change their website to reflect reality.* • Also shows that, for any significant exposure, immediate mass vaccination is far superior. • Ratio of cases and deaths: Ring/Mass ~ 180/1 *I have not checked CDC website in the last 10 days

17. A Recent Mathematical Model - Details(Kaplan -Yale, Craft - MIT, Wein - Stanford) • New York City • 1000 Persons initially infected • Compares Trace Vaccination (Ring Containment) and Immediate Mass Vaccination • Ring Containment: 324,000 cases, 97,000 deaths, control slow, epidemic still growing at 100 days • Mass Vaccination: 1,720 cases, 525 deaths, control fast, epidemic essentially over in 30 to 45 days • Also demonstrates limited value and great difficulties with quarantine and isolation of susceptibles and the asymptomatic

18. Kaplan Unpublished

19. Ring May Be More Myth than Reality • Kaplan, Wein & Craft - (In Press) • Central & West Africa eradication data recalculated. • Growing levels of population immunity fully explain the decline in new cases. • Bicknell Conversations with Lane, Margolis and Bloem • “We went into a village where there was a case and assumed everyone was a contact” • That’s local mass vaccination • Prof. Fenner - Surveillance, finding new cases, was critical. Then the response was local mass vaccination. • Conclusion: Contact tracing, isolation, quarantine and ring vaccination seems to have been more the exception than the rule.

20. Plausible US Scenario after 40 days(Play with the model ask wbicknel@bu.edu) • 5 terrorists each travel to 3 urban areas • 200 close contacts per city • 20% of contacts infected (40 cases/site) • 20% mortality • 5% of infected contacts travel to other cities • 1ary contacts infect 9 others, 2ary 5, 3ary 3 • Cities & Towns - 1,600 (21 by day 11) • Smallpox Cases - 114,000 • Smallpox Deaths - 22,000

21. Very Bad/Extreme Case ScenarioFirst 40 days • 10 terrorists each travel to 5 different urban areas • 500 close contacts per city • 40% of contacts infected (200 cases/site) • 30% mortality • 5% of infected contacts travel to other cities • 1ary contacts infect 10 others, 2ary 7, 3ary 4 • Cities & Towns - 40,000 (100 by day 11, then 1000s) • Smallpox Cases - 3,600,000 • Smallpox Deaths - 1,000,000

22. Ring Containment, Isolation & Quarantine • Eradication was accomplished in populations with high and growing population immunity, relatively low mobility and without malicious intent - A MAGNIFICANT ACHIEVMENT. • Terrorism today is different • Malicious intent • Low to absent immunity • Highly mobile terrorists and a more mobile population • Transmission to 2 or 3 - unrealistically low (Meltzer, et al) • The 4 day window - may not exist and not really relevant • Vaccination within the window not likely • Widespread isolation & quarantine - A near hopeless task, chaos and possible national shutdown • In brief - A plan that cannot work in a terrorist scenario and saw far less use in the eradication years than is commonly believed.

23. Ring Containment - Summary • Today, to the extent possible, with the first case or two, vaccinate probable contacts as soon as possible as you prepare for local or wider mass vaccination. • Consider contact tracing, isolation and quarantine if: • residual cases in an environment with high population immunity • an isolated exposure, particularly if there is high population immunity • Inadequate for a mobile population, with low to absent immunity and a malicious exposure in multiple cities • For controlling secondary spread in other countries - not a primary tool

24. The Magnitude of an Attack • Plan for the worst, hope for the best • Malicious and well executed • Multiple terrorists, Multiple cities

25. The Vaccine • It works and works well • There is plenty for everyone in the US and will be lots more • It is has more side effects including deaths than other vaccines currently in wide use • Who dies and who has the most severe side effects? Children 9 and under (NEJM, p1202, 11/27/69. • Accidental inoculation most common kid to kid • About 80% of the serious complications and deaths (1968 data) avoided if children not vaccinated • Teen and adult deaths extremely rare (CDC, Israel & US military & 1968 data) • Semi-permeable membrane dressing prevents 95 to 99% of viral shedding (Dr. Belshe, 5/8/01 at CDC) • Atopic dermatitis tricky (avoiding children helps a lot) • New and old vaccine probably similar complications • VIG good for many but not all complications

26. New Vaccines • Acambis -Replicating, not attenuated • Intended to mimic NYBH • Expect similar side effects • License on a fast track • Japanese LC16m8 - Replicating, attenuated • Fewer & less severe side effects • Still not OK for immunocompromised • Earliest, if developed 2005+ • Modified Vaccinia Ankara (MVA), Live non-replicating • Intention is OK for everyone • Earliest 2005+ • LC16m8 & MVA - Can we be really sure they will be effective in humans? How to know?

27. Vaccine Issues - 1 • Immunocompromised are at the highest risk of vaccine complications and of death from smallpox • Pre-exposure vaccination done with forethought provides a calm atmosphere where education and precautions can be assured • And if an attack, counseled to self isolate with selective vaccination based on well thought out criteria • Post-exposure will be in crisis with ability to protect the immunocompromised from complications greatly decreased: • Many will want to be vaccinated and not reveal their status • Our ability to identify and protect very limited when in crisis • Deaths from vaccine complications can be expected to exceed pre-exposure PLUS more smallpox deaths in the immunocompromised

28. Vaccine Issues - 2 • Accidental vaccination of contacts of vaccinees • Non-immunocompromised • Immunocompromised • Extremely rare • Almost exclusively in household contacts • Mostly children to children • Vaccine complications including deaths most common and most severe in children • Solution: • Pre-exposure do not immunize under age 9 • Use semi-permeable membrane dressings (Dr. Belshe) • Post-exposure drop to age 1 (and below if risk of exposure is high)

29. Vaccine Issues - 3 • 1968 data - Vaccination deaths in >15 all (2 of 14 million) would (should) be screened out today (aplastic anemia and leukemia) • If children <10 not vaccinated pre-exposure, careful screening and use of semi-permeable membrane dressing: • Severe complications and deaths should (my opinion) be at or below historical rates

30. Bifurcated Needle or Jet Injector? • Jet is faster • Jet can be difficult to maintain • Some evidence of inadvertent disease transmission • US currently off the table • CDC is developing a new, safer jet injector • Dr. Bruce Weniger is the US expert at CDC

31. Dilute Vaccine Lasts 180+ Days From Dr. Belshe ACIP CDC Presentation May 8, 2002

32. US Position - Fall 01 to Mid 02 • Reality - Limited Vaccine, have to prioritize • Did not say this, rather gave false assurances that Ring, etc.would work • State Health Officers silent • Substantial federal and state bad judgment • Believe public must be reassured - WRONG • Know it won’t work but don’t want to rock the boat - WRONG • Fear of Loosing federal funds • Possibly realistic and, to the extent it is true, reveals a dangerous weakness in the federal process • And dangerous timidity on the part of state public health officials

33. Who should decide in the US?(US cultural bias) • Attack risk is unknowable • Personal risk can be illuminated • Citizens make decisions about everything from participating in research protocols to deciding between vaginal delivery and C-section, angioplasty and open heart surgery on a daily basis • Smallpox vaccination is no more difficult, arguably much simpler with far lower risks than many other choices • Let the citizen decide within the framework of thoughtful pre-exposure guidelines • Unfortunately, we have seen that relying on PH professionals in the US may not be safe - more reason let individuals decide for themselves • This slide expresses my opinion and is, culturally, very specific to the US. Many PH professionals disagree.

34. Why Voluntary Pre-Exposure Vaccination in the US? • Decreases consequences of an attack • May decrease likelihood of attack • Provides the best protection for the immunocompromised • Is low cost and relatively easy to do as part of ongoing care • Recognizes the limited surge capacity of US hospitals and near impossibility of quarantine • In case of attack • Makes containment & control much easier, whatever the strategy • Decreases panic and maintains order • Minimizes interruption of the nation’s normal business • Is realistic, has face validity and is easily understood by the professional and lay public • By decreasing the likelihood and severity of an attack may benefit the rest of the world • Will protect the most people at the lowest cost

35. Objections that were raised • Our overall medical care delivery system is inequitable. Therefore pre-exposure vaccination will unfairly protect those with health insurance • We cannot solve all social problems before protecting against terrorism • Wait for newer safer vaccines and/or better, simpler diagnostic methods • The country needs protection today. We must plan for and use tools we have while developing better tools • We can’t vaccinate unless we are prepared to vaccinate the rest of the world • US vaccination, to the extent it decreases the likelihood of our being attacked , deceases risk to other countries. Many other countries have or are acquiring vaccine. This is fundamentally a foreign policy and foreign assistance question • A rational terrorist won’t use smallpox as it will boomerang • Let’s hope this is correct. However, it is irrational to apply our logic to terrorists

36. Inhibit the epidemiologic pump & first protect those most at risk • First responders, at a minimum, should include ALL staff of hospitals, clinics and physicians’ offices (~ 5.5 million people) • The definition of first responder & priority for vaccination should be determined by each state: • Which health workers? • Who in the executive branch? • Fire and police? • Essential public service providers? • Media crews? • The Federal Government decides for itself - 1,000,000 doses going to the army (NYT Oct 5)

37. First - a Measured Trial • Resolve liability issues • Careful guidelines to protect immunocompromised • Vaccinate 500,000 first responders (We’ve already vaccinated over 11,000 civilians since 1983, plus many military in the US until ‘90 and Israel until ‘96) • Use first responder volunteers to donate blood for VIG production • Observe vaccine complications very carefully • Revise guidelines and approach as indicated • Repeat with 1 to 2,000,000 first responders • Observe with care and revise as indicated • Vaccinate balance of first responders

38. Then - Expand to the general population • VIG now widely available • Public education as to risks and benefits of vaccination taking care to honestly and carefully distinguish between very serious/very rare and not so serious and far more common complications • Informed consent • Greatly reduce complications and deaths by restricting vaccination to: • Persons older than 9 years • Persons who are not immunocompromised and do not have other disqualifying conditions • Urge vaccinees to: • Announce their intent to family, friends and co-workers • Use appropriate dressing • Possibly consider avoiding crowds

39. Roles & Responsibilities • CDC • Safety guidelines for pre- and post-exposure vaccination - NOT the societal or individual risk decision • Technical assistance on request • Guidelines for pre- and post-exposure state action • States • Determine risk for their state • Make state-specific plans and recommendations • Who are first responders? • Pre-exposure guidance for general public • Post-exposure planning • Individuals • Assess their own risk • Opt or decline pre-exposure vaccination

40. My Recommendations & Conclusions for the US • CDC (analogous to WHO) guidance for • Pre-exposure vaccination • Post-exposure vaccination • State planning frameworks • CDC technical assistance (as capacity allows) • State (analogous to countries) control (nb federal reportable diseases) • Individual choice • Assessment of risk and benefit in the US should rest with those who have the risk - Citizens • Provides the most protection, at the lowest cost, with the least chaos, and recognizes that response will and must primarily be a local and state responsibility • Pre-exposure voluntary vaccination protects against a specific threat and puts prevention first. This is what public health and responsible government are all about

41. Likely Results of Pre-Exposure Vaccination • Based on survey data, 50% to 70% of population will opt for vaccination • Very rare serious complications and deaths • Decreased risk to the immunocompromised from vaccination and smallpox • Trained vaccinators and supplies in place in case of attack • Possible decreased likelihood of attack • Containment and control far easier in case of attack • Hospitals and the health care system not overwhelmed • Panic, disorder and the interruption of essential services and activities minimized • Known specific preventive steps taken before a terrorist attack • The public has an example of sound proactive public health

42. Public Trust • Whatever is done, it is vital that actions, including discussions, take place in a way that builds public trust • Inappropriate secrecy, silence or recommendations that do not make sense erode public trust • The responses of the federal government and state health departments to bioterrorism provide an opportunity to build trust and understanding of the importance of public health • Our response to smallpox and bioterrorism, if done with humility, openly and non-defensively, can be a win for everyone, protecting the public’s health and strengthening the public health system

43. Liability • This is a big US issue • A combination of federal, state and private actions are well on the way to solving the pre-exposure liability problem • and will vary in other countries • Other Countries • A function of law and custom • Let’s hope few are as litigious as the US!

44. Worldwide - What to do? • Country Specific Risk & Response Profile Based on: • Risk of Direct Attack • Risk of Secondary Spread • Strength of Medical Care & PH Delivery System • HIV/AIDS Prevalence • Opportunity Costs • Economic & Social Consequences • Cultural Values • Wealth

45. Different Strokes for Different folks • Not flippant - circumstances vary greatly • Canada and Mexico • Ireland • Israel and the Occupied Territories • Bhutan • Singapore • Cambodia • Australia • Lesotho • The Marshall Islands

46. National Policy Options 1 - Countries at high risk of attack 2 - Countries at high risk of secondary spread 3 - Countries at moderate risk of secondary spread 4 - Countries at lower risk of secondary infection 5 - Countries with special risks

47. High risk of attack • Minimum package: Voluntary vaccination of eligible medical and public health first responders. Stockpile vaccine sufficient for the entire population and stockpile VIG sufficient to manage probable vaccine complications. • Maximum package: Minimum package plus voluntary vaccination of all remaining first responders. Make the vaccine available on a voluntary basis to the general public.

48. High risk of secondary spread • Minimum package: Stockpile vaccine sufficient for 50% to 100% of the population. Stockpile VIG sufficient to manage probable vaccine complications. • Maximum package: Minimum package plus vaccinate medical and public health first responders.

49. Moderate risk of secondary spread • Minimum package: Stockpile sufficient vaccine and VIG to initiate but not complete widespread vaccination. Vaccine and VIG stockpile sufficient for 10% to 25% of the national population. • Maximum package: Minimum package plus vaccinate a limited number of medical and public health first responders.

50. Lower risk of secondary spread • Minimum Package: Assure rapid availability of vaccine and VIG from sources in country or abroad. • Maximum package: Stockpile vaccine and VIG sufficient for 10% of the population. Vaccinate a limited number of medical and public health first responders.